Hypertension is the leading cause of cardiovascular disease in patients on hemodialysis. A major contributor to hypertension in these patients is chronic volume expansion. Hemodialysis is often inadequate to remove all the excess fluid accumulated because of intradialytic hypotension, the most common acute complication of hemodialysis, occurring in 20–50% of all treatments (Bregman H, Daugirdas J T and Ing T S. in Handbook of Dialysis, second ed., Little, Brown and Co.(1994): chapter 9; Henrich, W L. Hemodynamic instability during hemodialysis. Kidney Int. (1986); 30: 605–612; Shaldon S. Progress from Haemodialysis. Nephron (1981); 27: 2–6; Lazarus J. M., Denker B. M., Owen W. F. in The Kidney, fifth ed., W. B. Sauders Company (1996): 56). Sequelae of intradialytic hypotension include general malaise, dizziness, muscle cramping, and vomiting, as well as the potentially lethal complications of myocardial ischemia and vomiting, as well as the potentially lethal complications of myocardial ischemia and cerebral hypoperfusion. In addition, hypotensive events impede the efficiency of fluid removal during the treatment. The primary cause of intradialytic hypotension is believed to be the rapid removal of intravascular volume (Bregman H, Daugirdas J T and Ing T S. in Handbook of Dialysis, second ed., Little, Brown and Co. (1994): chapter 9; Henrich, W L. Hemodynamic instability during hemodialysis. Kidney Int. (1986); 30: 605–612; Keshaviah, P., Jacobson, H. R., Striker G. E., Klahr S. in The. Principles and Practice of Nephrology, second ed., Mosby (1995): chapter 95), possibly exacerbated by a diminished baroreflex response (Campese V M, Romoff M S, Levitan D, Lane K and Massry S G. Kidney Int. (1981); 20: 246–253; Ziegler M G, Kennedy B, Morrissey E and O'Connor D T. Norepinephrine clearance, chromogranin A and dopamine beta hydoxylase in renal failure. Kidney Int. (1990); 37: 1357–1362; Kersh, E S, Kronfield S J, Unger A, Popper R W, Cantor S and Cohn K. Autonomic insufficiency in uremia as a cause of hemodialysis-induced hypotension. N. Eng. J. Med. (1974); 290: 650–653; Ewing D J and Winney R. Autonomic function in patients with chronic renal failure on intermittent hemodialysis. Nephron (1975); 15: 424–429; Lilley J J, Golden J and Stone R A. Adrenergic regulation of blood pressure in chronic renal failure. J. Clin. Invest. (1976); 57: 1190–1200; Nies A S, Robertson D and Stone W J. Hemodialysis hypotension is not the result of uremic peripheral neuropaihy. J. Lab. Clin. Med. (1979); 3: 395–402; Mallamaci C Z, Ciccarelli M and Briggs J D. Autonomic function in uremic patients treated by hemodialysis or CAPD and in transplant patients. Clin. Nephrol. (1986); 25: 175–180; Nakashima Y, Fetnat M F, Satoru N, Textor S C, Bravo E L and Tarazi R C. Localization of autonomic nervous system dysfunction in dialysis patients. Am. J. Nephrol. (1987); 7: 375–381; Daul A E, Wang X L, Miche M C and Brodde O. Arterial hypotension in chronic hemodialyzed patients. Kidney Int. (1987); 32: 728–735; Henrich W L. Hemodynamic instability during dialysis. Kidney Int. (1986); 30: 605–612).
Defense of blood pressure involves, in part, baroreflex-mediated autonomic afferent signaling to the posterior pituitary. This stimulatory signal causes a release of arginine vasopressin (AVP), which stimulates arterial smooth muscle to vasoconstrict. Two mechanisms appear to inhibit this pathway during hemodialysis: autonomic neuropathy and acute decreases in plasma osmolality. Autonomic neuropathy, a common co-morbid condition in many hemodialysis patients, can hinder the initial stimulatory signal for AVP secretion. The acute decrease in plasma osmolality that results from solute removal during hemodialysis directly inhibits AVP secretion. Therefore, it is our hypothesis that an AVP deficiency, due to an inappropriate decrease in secretion, contributes to the hypotensive episodes during hemodialysis. Although hypotension is a frequent complication on hemodialysis, hypertension is frequent between dialysis treatments. Chronic hypertension is a potent risk factor for cardiovascular morbidity and mortality. Cardiovascular mortality is the major contributor to the 40% five-year survival in ESRD patients.
The current treatment for intradialytic hypotension is volume infusion and/or a decrease in the rate of fluid removal. However, this solution abandons one of the principal objectives of hemodialysis, the removal of excess water ingested between treatments. The expedient of leaving patients with end-stage renal disease in a state of volume expansion in order to avoid intradialytic hypotension can cause or exacebate interdialytic hypertension. Ideally, treatment to facilitate dialytic fluid removal and ameliorate interdialytic hypertension would maintain blood pressure and permit adequate fluid removal. Exogenous AVP, a potential therapy for patients with a history of intradialytic hypotension, may diminish the number of hypotensive episodes and minimize the need for this expedient.
AVP is an intriguing hormone because it contributes little to blood pressure maintenance under normal conditions (Grollman A and Geiling E M K. J. Pharmacol. & Exper. Therap. (1932); 46: 447–460; Graybiel A and Glendy R E. Am. Heart J. (1941); 21: 481–489; Wagner H N and Braunwald E. J. Clin. Invest. (1956); 35: 1412–1418), but becomes critical when arterial pressure is threatened (Wagner H N and Braunwald E. J. Clin. Invest. (1956); 35: 1412–1418 Aisenbrey G A, Handelman W A, Arnold O, Manning M and Schrier R W. J. Clin. Invest. (1981); 67: 961–968; Schwartz J and Reid I A. Endocrinology (1981); 108: 1778–1780; Schwartz J, Keil L C, Maselli J and Reid I A. Endocrinology (1983); 112: 234–238). When AVP fails to be secreted by bororeflex-mediated stimulation, hypotension and inappropriate vasodilation ensue. This most commonly occurs in the setting of autonomic neuropathy, where we (Kaufmann H, Oribe E and Oliver J A. Plasma endothelin during upright tilt: relevance for orthostatic hypotension? Lancet (1991); 338: pp. 1542–45) and others (Zerbe R L, Henry D P and Robertson G L. Vasopressin response to orthostatic hypotension. Etiologic and clinical implications. Am. J. Med. (1983); 74: pp. 265–271) have shown that hypotension fails to induce AVP secretion. Recently, we have also found that septic shock is characterized by a defect in bororeceptor reflex-mediated secretion of AVP (Landry D W, Levin H R, Gallant E M, Ashton R C, Seo S, D'Allesandro D, Oz, M C and Oliver J A. Vasopressin deficiency contributes to the vasodilation of septic shock. Circ. (1997); 95: pp 1122–1125).
AVP hypersensitivity has been reported in the setting of autonomic neuropathy, and we have recently demonstrated that AVP deficiency and hypersensitivity also characterize vasodilatory septic shock (Landry D W, Levin H R, Gallant E M, Ashton R C, Seo S, D'Alessandro D, Oz M C and Oliver J A). Vasopressin deficiency contributes to the vasodilation of septic shock. Circ. (1997); 95: 1122–1125). These observations suggest that hypotensive episodes associated with AVP deficiency are likely to respond to very low doses of exogenous hormone.
Secretion of AVP is Defective in Hemodialysis Patients
AVP is released from the posterior pituitary through activation of the baroreflex by a decrease in arterial pressure or through activation of hypothalamic osmoreceptors by a rise in serum osmolality. A large body of evidence suggests that both stimuli of AVP secretion are compromised during dialysis.
Autonomic Dysfunction
Autonomic neuropathy is a common co-morbid condition in patients with renal failure requiring dialysis (Campese V M, Romoff M S, Levitan D, Lane K and Massry S G. Kidney Int. (1981); 20: 246–253; Ziegler M G, Kennedy B, Morrissey E and O'Connor D T. Norepinephrine clearance, chromogranin A and dopamine beta hydoxylase in renal failure. Kidney Int. (1990); 37: 1357–1362; Kersh, E S, Kronfield S J, Unger A, Popper R W, Cantor S and Cohn K. Autonomic insufficiency in uremia as a cause of hemodialysis-induced hypotension. N. Eng. J. Med. (1974); 290: 650–653; Ewing D J and Winney R. Autonomic function in patients with chronic renal failure on intermittent hemodialysis. Nephron (1975); 15: 424–429; Lilley J J, Golden J and Stone R A. Adrenergic regulation of blood pressure in chronic renal failure. J. Clin. Invest. (1976); 57: 1190–1200; Nies A S, Robertson D and Stone W J. Hemodialysis hypotension is not the result of uremic peripheral neuropathy. J. Lab. Clin. Med. (1979); 3: 395–402; Mallamaci C Z, Ciccarelli M and Briggs J D. Autonomic function in uremic patients treated by hemodialysis or CAPD and in transplant patients. Clin. Nephrol. (1986); 25: 175–180; Nakashima Y, Fetnat M F, Satoru N, Textor S C, Bravo E L and Tarazi R C. Localization of autonomic nervous system dysfunction in dialysis patients. Am. J. Nephrol. (1987); 7: 375–381; Daul A E, Wang X L, Miche M C and Brodde O. Arterial hypotension in chronic hemodialyzed patients. Kidney Int. (1987); 32: 728–735; Henrich W L. Hemodynamic instability during dialysis. Kidney Int. (1986); 30: 605–612). In fact, 37% of patients on hemodialysis in the USA have diabetes mellitus, a disease in which one of the major manifestations is autonomic neuropathy. As baroreflex-mediated secretion requires intact autonomic afferent pathways, many patients on hemodialysis may have insufficient AVP release in response to decreased circulating blood volume.
Hypo-osmolality
Patients with end-stage renal disease generally demonstrate a baseline hyperosmolality in their intra- and extracellular copmpartments. Hemodialysis causes a rapid fall in plasma osmolality, which can suppress AVP secretion even in the setting of hypovolemia. In fact, there are significant data showing that plasma AVP levels decrease or remain unchanged during dialysis despite decreases in blood pressure due to fluid removal (Hegbrandt J, Thysell J, Martensson L, Ekman R and Boberg U. Changes in plasma levels of vasoactive peptides during sequential bicarbonate hemodialysis. Nephron (1993); 63: 309–313; Shimamoto K, Ikuo W and Miyahara M. A study of plasma vasopressin in patients undergoing chronic hemodialysis. J. Clin. Endocrin. Met. (1977); 45: 714–720; Horky K, Sramkova J, Lachmanova J, Tomasek R and Dvorakova J. Plasma concentration of antidiuretic hormone in patients with chronic renal insufficiency on maintenance dialysis. Horm. Metab. Res. (1979); 11: 241–246; Caillens H, Prusczynski W, Neyrier A, Ang K, Rousselet F and Ardaillou R. Relationship between change in volemia at constant osmolality and plasma antidiuretic hormone. Miner. Electrolyte Metab. (1980); 4: 161–171; D'Amore T F, Wauters J P, Waeber B, Nussberger J and Brunner H R. Response of plasma vasopressin to changes in extracellular volume and/or osmolality in patients on maintenance hemodialysis. Clin. Nephrol. (1985); 23: 299–302; Iitake K, Kimura T, Matsui K, Ota K, Masaru S, Inoue M and Yoshinaga K. Effect of hemodialysis on plasma ADH levels, plasma renin activity and plasma aldosterone levels, in patients with end-stage renal disease. Acta Endocrin. (1985); 110: 207–213; Jawadi M H, Ho L S, Dipette D and Ross D L. Regulation of plasma arginine vasopressin in patients with chronic renal failure maintained on hemodialysis. Am. J. Nephrol. (1986); 6: 175–181; Rosansky S J, Rhinehart R and Shade R. Effect of osmolar changes on plasma arginine vasopressin (PAVP) in dialysis patients. Clin. Nephrol. (1991); 35: 158–164; Shiota J, Kubota M, Hamada C and Koide J. Plasma atrial natriuretic peptide during hemodialysis with or without fluid removal. Nephron (1990); 55: 283–286; Hegbrandt J, Thysell J, Martensson L, Ekman R and Boberg U. Changes in plasma levels of vasoactive peptides during standard bicarbonate hemodialysis. Nephron (1993); 63: 303–308). Moreover, it has long been known that intravenous infusion of hyperosmotic solutions, such as mannitol or hypertonic saline, greatly ameliorates intradialytic hypotension (Henrich W L, Woodard T D, Blachley J D, Gomez-Sanchez C, Pettinger W and Cronin R E. Role of osmolality in blood pressure stability after dialysis and ultrafiltration. Kidney Int. (1980); 18: 480–488), possibly by facilitating AVP secretion in addition to augmenting circulating volume.